Phosphatidylinositol 3-kinase-dependent activation of trypsinogen modulates the severity of acute pancreatitis

Citation
Vp. Singh et al., Phosphatidylinositol 3-kinase-dependent activation of trypsinogen modulates the severity of acute pancreatitis, J CLIN INV, 108(9), 2001, pp. 1387-1394
Citations number
34
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Medical Research General Topics
Journal title
JOURNAL OF CLINICAL INVESTIGATION
ISSN journal
0021-9738 → ACNP
Volume
108
Issue
9
Year of publication
2001
Pages
1387 - 1394
Database
ISI
SICI code
0021-9738(200111)108:9<1387:P3AOTM>2.0.ZU;2-R
Abstract
Intra-acinar cell activation of digestive enzyme zymogens including trypsin ogen is generally believed to be an early and critical event in acute pancr eatitis. We have found that the phosphatidylinositol 3-kinase inhibitor wor tmannin can reduce the intrapancreatic activation of trypsinogen that occur s during two dissimilar experimental models of rodent acute pancreatitis, s ecretagogue- and duct injection-induced pancreatitis. The severity of both models was also reduced by wortmannin administration. In contrast, the NF-k appaB activation that occurs during the early stages of secretagogue-induce d pancreatitis is not altered by administration of wortmannin. Ex vivo, cae rulein-induced trypsinogen activation is inhibited by wortmannin and LY2940 02. However, the cytoskeletal changes induced by caerulein were not affecte d by wortmannin. Concentrations of caerulein that induced ex vivo trypsinog en activation do not significantly increase phosphatidylinositol-3,4-bispho sphate or phosphatidylinositol 3,4,5-trisphosphate levels or induce phospho rylation of Akt/PKB, suggesting that class I phosphatidylinositol 3-kinases are not involved. The concentration of wortmannin that inhibits trypsinoge n activation causes a 75% decrease in phosphatidylinositol 3-phosphate, whi ch is implicated in vesicle trafficking and fusion. We conclude that a wort mannin-inhibitable phosphatidylinositol 3-kinase is necessary for intrapanc reatic activation of trypsinogen and regulating the severity of acute pancr eatitis. Our observations suggest that phosphatidylinositol 3-kinase inhibi tion might be of benefit in preventing acute pancreatitis.